US4258053A - Thienyl-prostaglandins and process for their manufacture - Google Patents

Thienyl-prostaglandins and process for their manufacture Download PDF

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Publication number
US4258053A
US4258053A US06/136,982 US13698280A US4258053A US 4258053 A US4258053 A US 4258053A US 13698280 A US13698280 A US 13698280A US 4258053 A US4258053 A US 4258053A
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multiplet
sub
ppm
thienyl
formula
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Wilhelm Bartmann
Gerhard Beck
Dieter-Bernd Reuschling
Karl Seeger
Hermann Teufel
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Hoechst AG
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Hoechst AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/93—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems condensed with a ring other than six-membered
    • C07D307/935—Not further condensed cyclopenta [b] furans or hydrogenated cyclopenta [b] furans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/32—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/54—Quaternary phosphonium compounds
    • C07F9/5407—Acyclic saturated phosphonium compounds
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09J—ADHESIVES; NON-MECHANICAL ASPECTS OF ADHESIVE PROCESSES IN GENERAL; ADHESIVE PROCESSES NOT PROVIDED FOR ELSEWHERE; USE OF MATERIALS AS ADHESIVES
    • C09J7/00—Adhesives in the form of films or foils
    • C09J7/10—Adhesives in the form of films or foils without carriers

Definitions

  • the present invention relates to thienyl-prostaglandins and to a process for their manufacture.
  • Prostaglandins are a group of natural substances which have been isolated from various animal tissues. They are responsible for a large number of physiological effects in mammals.
  • the natural prostaglandins have a carbon skeleton of generally 20 carbon atoms and differ chiefly in a major or minor content of hydroxyl groups or double bonds in the cyclopentane ring (the structure and action of prostaglandins are described, inter alia, in M. F. Cuthbert "The Prostaglandins, Pharmacological and Therapeutic advances", William Heinemann Medical Books, Ltd., London 1973).
  • the present invention provides prostanoic acid analogs which do not occur naturally of the general formula I ##STR1## which comprises both the optically active compounds of the natural configuration and the racemic compounds and in which:
  • R 1 and R 2 each is hydrogen or a hydroxyl group, R 1 and R 2 being different,
  • R 3 is a ⁇ - or ⁇ -thienyl radical or a ⁇ - or ⁇ -thienylmethyl radical which may be substituted 1 to 3 times in the nucleus by halogen, trifluoromethyl and/or alkyl or alkoxy having 1 to 6 carbon atoms each and/or by a phenyl radical which is unsubstituted or substituted 1 to 3 times by halogen, trifluoromethyl and/or alkyl or alkoxy having 1 to 5 carbon atoms, or R 3 is a benzo[b]thiophene radical which may be substituted 1 to 3 times by trifluoromethyl, or R 3 , is a cyclopentano-[b]-thiophene radical or a cyclohexano[b]thiophene radical,
  • X is a straight-chain or branched alkylidene or alkylene group having 1 to 7 carbon atoms or a straight-chain or branched alkoxyalkylene group of 2 to 8 carbon atoms,
  • the invention further relates to a process for the manufacture of the new analogs of prostanoic acids of the formula I, their physiologically acceptable salts with organic and inorganic bases and their esters as well as to pharmaceutical preparations containing these active compounds.
  • R 3 Of the groups mentioned for the substituent R 3 are preferred the unsubstituted ⁇ - or ⁇ -thienyl as well as ⁇ - or ⁇ -thienylmethyl radicals, further ⁇ - or ⁇ -thienyl and thienylmethyl radicals which are substituted 1 to 3 times by chlorine, trifluoromethyl and/or methoxyl or methyl.
  • Preferred substitutents of the thiophene radicals are also the phenyl group which is unsubstituted or substituted respectively 1 to 3 times by halogen, especially chlorine, by trifluoromethyl groups and/or by alkoxy having 1 to 3 carbon atoms, especially methoxyl or methyl.
  • Preferred substituents R 3 are furthermore the benzo[b]thienyl radical which is unsubstituted or substituted 1 to 3 times by the trifluoromethyl group, the cyclopentano[b]thienyl and the cyclohexano[b]thienyl radical.
  • the process according to the invention starts from the aldehyde of the formula III which is prepared according to German Offenlegungsschrift DT-OS No. 24 16 193 from the primary bicyclic alcohol of the formula II ##STR10## by oxidation with an oxidizing agent, for example with a complex of thioanisol and chlorine or the complex compound of CrO 3 and pyridine in an aprotic solvent at temperatures ranging between -50° C. and room temperature, preferably -30° C. and -5° C. in an inert atmosphere.
  • Suitable solvents are, in this case, for example aromatic hydrocarbons, such as benzene or toluene or for example chlorinated aliphatic hydrocarbons, such as carbon tetrachloride.
  • the aldehyde of the formula III is reacted by the method of Horner, Wittig and Emmons with a phosphonic acid ester of the formula IV to give an unsaturated ketone of the formula V; a preferred embodiment of the reaction comprising preparing the sodium salt of the phosphonic acid ester by means of sodium hydride in glycol dimethyl ether, then adding the aldehyde of the formula III and allowing the reaction to take place at room temperature for 2 to 6 hours.
  • a phosphonic acid ester of the formula IV may be prepared by reacting an ester of the formula R 3 --OX--CO 2 --alkyl in the presence of excess butyl-lithium and methylphosphonic acid dimethyl ester (for example, by the method of Corey, J. Am. Chem. Soc. 88, 5654 (1966)).
  • the epimeric mixture of alcohols of the formula VI is obtained from the ketone of the formula V by reduction with a complex metal hydride, preferably with an alkali metal boranate or zinc boranate in ethereal solution, preferably at a temperature within the range of from 0° C. to room temperature.
  • the zinc boranate is preferably prepared in situ from zinc chloride and sodium borohydride in absolute ethereal solution.
  • the alcohols of the formula VI are particularly suitable for separation into the S-epimers and R-epimers, preferably by means of column chromatography on silica gel, but the further reactions can also be carried out with the mixture of epimers and the separation of the epimers can be carried out at the stage of the end product.
  • the subsequent hydrolytic splitting of the p-phenylbenzoyl group of the alcohol of the formula VI is carried out in an alcoholic medium with the aid of an alkali metal carbonate or an alkaline earth metal carbonate.
  • An advantageous embodiment consists of treating the alcohol or the corresponding mixture of epimers in absolute methanol at room temperature with anhydrous potassium carbonate, a diol of the formula VII being formed.
  • the di-tetrahydropyranyl ether of the formula VIII is prepared, generally in an ethereal or benzene solution of the alcohols of the formula VII, in the presence of a customary acid catalyst, such as, for example, toluenesulfonic acid.
  • the resulting compound of the formula VIII is reduced to a lactol of the formula IX by means of a complex aluminum hydride in an aprotic solvent. It is preferable to use diisobutyl-aluminum hydride in toluene at -60° C. to -70° C.
  • the resulting lactone of the formula IX can be reacted by the method of Wittig, without further purification, to give a carboxylic acid of the formula X.
  • the preferred embodiment of this process follows the instructions given in J. Org. Chem. 28, 1128 (1963).
  • the protective ether groups in a compound of the formula X are split off by mild acid hydrolysis of the tetrahydropyranyl ether groups by means of an aqueous organic acid, preferably in 2% strength aqueous-alcoholic oxalic acid solution at 20° C. to 50° C., or by heating for 1 to 2 hours in 60% to 70% strength acetic acid at 40° C., a carboxylic acid of the formula I being formed.
  • a separation of the 15-S-epimer from the 15-R-epimer is preferably carried out after formation of a compound of the formula I.
  • the separation is preferably carried out on silica gel (Merck, 70-230 mesh), the 15-S-epimer usually being eluted after the 15-R-epimer.
  • a suitable eluting agent for the separation by column chromatography of the compounds of the formula I is a mixture of chloroform and glacial acetic acid in the ratio of 97.5:2.5.
  • the compounds of the formula I may optionally be converted according to usual methods into physiologically acceptable salts or esters.
  • the compounds of the invention of the formula I are analogs of prostanoic acids which do not occur naturally and which can be used as medicaments by virtue of their pharmacological effects.
  • the natural prostaglandins PGE 1 ⁇ , PGE 2 ⁇ or PGA 2 have the disadvantage that they are so quickly deactivated in a living body that their pharmacological action cannot be maintained for the time required for therapy.
  • the compounds of the invention are distinguished by a longer duration of action and a stronger effect.
  • the compounds of the invention have a hypotensive and diuretic action, and may be used as abortifacients and contraceptives, as agents for inhibiting secretion of the gastric juices, and as agents against gastric ulcers and asthma.
  • the compounds of the invention are especially suitable contraceptives for human beings and especially suitable agents for synchronization of the estrus in different animal species.
  • the compounds of the invention may be used in the form of the free acid, physiologically tolerable inorganic or organic salts, or as esters with an aliphatic, cycloaliphatic or araliphatic alcohol.
  • suitable salts are benzylammonium, triethanolammonium or morpholine salts and alkali metal salts
  • the preferred esters are those with saturated, branched or straight-chain, lower aliphatic alcohols, for example, methyl, ethyl, propyl, butyl or pentyl esters, and benzyl esters.
  • the acids and salts as well as the esters may be used in the form of aqueous solutions or suspensions, or solutions in pharmacologically suitable organic solvents, for example, monohydric or polyhydric alcohols, dimethylsulfoxide or dimethyl formamide.
  • pharmacologically suitable organic solvents for example, monohydric or polyhydric alcohols, dimethylsulfoxide or dimethyl formamide.
  • a pharmaceutically suitable polymeric carrier for example, polyvinylpyrrolidone, may also be used.
  • the preparation of the invention may be in a form suitable for administration, for example, infusion solutions or injection solutions, tablets, as well as preparation which can be applied locally, for example, creams, emulsions, suppositories and aerosols.
  • the preparations of the invention may comprise compounds of the formula I, salts or esters thereof, as the only active substance, or may also comprise one or more other pharmacologically active substances, for example, diuretics or antidiabetics.
  • the single dose to be administered to animals, especially to cattle, horses or sheep is 0.05 to 50 mg, preferably 0.5 to 30 mg.
  • the daily dose is 0.1 to 100 mg, preferably 1 to 60 mg.
  • infusion solutions are especially suitable.
  • the dose is, for example, 0.2 to 0.5 mg per 2 hours.
  • the reaction mixture was then poured into an ice cooled solution of 600 ml of 15 strength HCl and 1.51 l of diisopropyl ether.
  • the white precipitate of 24 g which was thrown down was filtered off on as large a filter as possible and was washed with ether.
  • the filtrate was poured into a separating funnel and the organic phase was separated off, dried and concentrated, at not more than +15° C., to a volume of approx. 750 ml. After cooling well, the crystals which have precipitated were filtered off (5 g) and were combined with the filter residue.
  • This compound was prepared in an analogous manner from III and the phosphonate 1c.
  • This compound was prepared from III and the phosphonate 1d.
  • the 15-S and 15-R-epimers can be separated easily by column chromatography with pure diethyl ether.
  • This compound was obtained in a 86% yield after preparation from 5b, according to Example 6a.
  • IR-spectrum OH-bands at 3400 (broad), no C ⁇ O bands.
  • the signal at 5.8-6.2 ppm can be removed by H/D exchange.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Compounds Containing Sulfur Atoms (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
US06/136,982 1975-06-05 1980-04-03 Thienyl-prostaglandins and process for their manufacture Expired - Lifetime US4258053A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE2524955A DE2524955C3 (de) 1975-06-05 1975-06-05 Neue Thienyl-Prostaglandine und Verfahren zu ihrer Herstellung
DE2524955 1975-06-05

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US (1) US4258053A (enrdf_load_stackoverflow)
JP (3) JPS527954A (enrdf_load_stackoverflow)
AT (1) AT360671B (enrdf_load_stackoverflow)
AU (1) AU517489B2 (enrdf_load_stackoverflow)
BE (1) BE842687A (enrdf_load_stackoverflow)
CA (1) CA1086722A (enrdf_load_stackoverflow)
CH (1) CH625213A5 (enrdf_load_stackoverflow)
DE (1) DE2524955C3 (enrdf_load_stackoverflow)
DK (1) DK152675C (enrdf_load_stackoverflow)
ES (1) ES448387A1 (enrdf_load_stackoverflow)
FR (1) FR2313036A1 (enrdf_load_stackoverflow)
GB (1) GB1553914A (enrdf_load_stackoverflow)
HU (1) HU175238B (enrdf_load_stackoverflow)
IE (1) IE43849B1 (enrdf_load_stackoverflow)
IL (1) IL49716A (enrdf_load_stackoverflow)
IT (1) IT1061525B (enrdf_load_stackoverflow)
LU (1) LU75076A1 (enrdf_load_stackoverflow)
MX (1) MX3609E (enrdf_load_stackoverflow)
NL (1) NL188693C (enrdf_load_stackoverflow)
SE (2) SE430158B (enrdf_load_stackoverflow)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016153094A1 (ko) * 2015-03-26 2016-09-29 비스메르 주식회사 3-알콕시싸이오펜 유도체의 신규한 제조방법
CN106146455A (zh) * 2015-03-30 2016-11-23 维斯曼株式会社 3-烷氧基噻吩衍生物及其制备方法

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH04107991U (ja) * 1991-02-26 1992-09-17 テーダブリユ電気株式会社 ヘツドホン

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3931279A (en) * 1973-05-21 1976-01-06 The Upjohn Company 5-Oxa prostaglandin F2.sub.α analogs
US3932289A (en) * 1973-11-09 1976-01-13 Chevron Research Company Preparation of overbased carbonated sulfurized magnesium alkylphenates
US3956284A (en) * 1972-07-13 1976-05-11 Pfizer Inc. Heterocyclic 15-substituted-ω-pentanorprostoglandins
US3978229A (en) * 1974-04-11 1976-08-31 Ono Pharmaceutical Co., Ltd. Synergistic composition comprising PGF2.sub.α and PGE2
US4004021A (en) * 1973-01-31 1977-01-18 Imperial Chemical Industries Limited Cyclopentane derivatives
FR2200014B1 (enrdf_load_stackoverflow) 1972-09-27 1978-01-13 Ici Ltd

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3956284A (en) * 1972-07-13 1976-05-11 Pfizer Inc. Heterocyclic 15-substituted-ω-pentanorprostoglandins
FR2200014B1 (enrdf_load_stackoverflow) 1972-09-27 1978-01-13 Ici Ltd
US4004021A (en) * 1973-01-31 1977-01-18 Imperial Chemical Industries Limited Cyclopentane derivatives
US3931279A (en) * 1973-05-21 1976-01-06 The Upjohn Company 5-Oxa prostaglandin F2.sub.α analogs
US3932289A (en) * 1973-11-09 1976-01-13 Chevron Research Company Preparation of overbased carbonated sulfurized magnesium alkylphenates
US3978229A (en) * 1974-04-11 1976-08-31 Ono Pharmaceutical Co., Ltd. Synergistic composition comprising PGF2.sub.α and PGE2

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016153094A1 (ko) * 2015-03-26 2016-09-29 비스메르 주식회사 3-알콕시싸이오펜 유도체의 신규한 제조방법
CN106146455A (zh) * 2015-03-30 2016-11-23 维斯曼株式会社 3-烷氧基噻吩衍生物及其制备方法

Also Published As

Publication number Publication date
JPS61246181A (ja) 1986-11-01
HU175238B (hu) 1980-06-28
IL49716A (en) 1980-10-26
IT1061525B (it) 1983-04-30
SE445112B (sv) 1986-06-02
JPS61243075A (ja) 1986-10-29
GB1553914A (en) 1979-10-10
SE430158B (sv) 1983-10-24
SE7910057L (sv) 1979-12-06
JPS527954A (en) 1977-01-21
JPS6261593B2 (enrdf_load_stackoverflow) 1987-12-22
DE2524955C3 (de) 1981-12-03
IE43849L (en) 1976-12-05
IL49716A0 (en) 1976-08-31
AU517489B2 (en) 1981-08-06
DK152675C (da) 1988-10-31
DE2524955A1 (de) 1977-03-17
JPS6261592B2 (enrdf_load_stackoverflow) 1987-12-22
DE2524955B2 (de) 1981-02-12
CH625213A5 (enrdf_load_stackoverflow) 1981-09-15
DK152675B (da) 1988-04-11
FR2313036A1 (fr) 1976-12-31
MX3609E (es) 1981-03-31
SE7606318L (sv) 1976-12-06
ES448387A1 (es) 1977-08-01
AU1460176A (en) 1977-12-08
BE842687A (fr) 1976-12-08
DK248176A (da) 1976-12-06
NL188693C (nl) 1992-09-01
NL7605856A (nl) 1976-12-07
JPS6210233B2 (enrdf_load_stackoverflow) 1987-03-05
FR2313036B1 (enrdf_load_stackoverflow) 1979-06-29
ATA413676A (de) 1980-06-15
IE43849B1 (en) 1981-06-17
CA1086722A (en) 1980-09-30
AT360671B (de) 1981-01-26
LU75076A1 (enrdf_load_stackoverflow) 1977-03-07

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